Nucleotides Metabolism N N N N N N 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 Purine Pyrimidine O OH HO CH 2 HO Base 1´ 2´ 3´ 4´ 5´ Nucleoside 1´ 2´ 3´ 4´ 5´ Nucleotide Monophosphate 1´ 2´ 3´ 4´ 5´ 2´-Deoxyribonucleotide Monophosphate P O O O O O HO CH 2 Base P O O O O O OH HO CH 2 Base N N N H N NH 2 HN N N H N O H 2 N N H N O NH 2 Adenine Guanine Cytosine Thymine Uracil B a s e N u c l e o t i d e P u r i n e s P y r i m i d i n e s B a s e N u c l e o t i d e Adenosine Guanosine Cytidine Uridine Thymidine N H NH O O N H NH O O H 3 C N N N H N O HN N H N H N O O HN N H N H H N O O O HN NH O O N N N N O O CH 3 H 3 C CH 3 Hypoxanthine Xanthine Uric acid Pseudouracil 1,3,7-Trimethyl xanthine
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Nucleotides Metabolism
N
N N
N
N
N1
2
3
4
56 7
8
9 1
2
34
5
6
Purine Pyrimidine
O
OHHO
CH2HOBase
1´
2´3´
4´
5´
Nucleoside
1´
2´3´
4´
5´
NucleotideMonophosphate
1´
2´3´
4´
5´
2´-DeoxyribonucleotideMonophosphate
P
O
O
O O O
HO
CH2Base
P
O
O
O O O
OHHO
CH2Base
N
N NH
N
NH2
HN
N NH
N
O
H2N
NH
N
O
NH2
Adenine
Guanine
Cytosine
Thymine
Uracil
Base Nucleotide
Purines Pyrimidines
Base Nucleotide
Adenosine
Guanosine
Cytidine
Uridine
Thymidine
NH
NH
O
O
NH
NH
O
O
H3C
N
N NH
N
O
HN
NH
NH
N
O
O
HN
NH
NH
HN
O
O
OHN NH
O
O
N
N N
N
O
O
CH3H3C
CH3
Hypoxanthine Xanthine Uric acid Pseudouracil 1,3,7-Trimethylxanthine
Folic Acid
HN
N
N
N
HN
O
HN
O O
O
O
H2N
O
Folic Acid
Pterin
p-Aminobenzoicacid
Glutamate
N5
N10
SNH2
O
O
H2N
Sulfanilamide
HN
N
N
N
HNR
H2N
O
HN
N
N
N
HN
H2N
OR
H
HH
HN
N
N
N
HN
H2N
OR
H
HH
H
H
NADPNADPH
Folic Acid Dihydrofolate Tetrahydrofolate(THF)
Dihydrofolatereductase
NADPNADPH
Dihydrofolatereductase
HN
N
N
N
HN
O
HN
O O
O
O
H2N
O
Folic Acid
HN
N
N
N
N
O
HN
O O
O
O
H2N
NH2
Methotrexate
H3C
HN
N
N
N
HN
O
HN
O O
O
O
H2N
NH2
Aminopterin
N
N
OCH3
O
CH3
OH3C
NH2H2N
Trimethoprim
Folic Acid Metabolism
Tetrahydrofolate(THF)
HN
N
N
N
HNR
H2N
O H
H
HH
H
HN
N
N
HN
NR
H2N
O H2C
N5,N10-MethyleneTetrahydrofolate
Glycine+ NAD
CO2 + NH4+ NADH
Glycinecleavage enzyme
(Glycine synthase)
Serinehydroxymethyltransferase
Serine
Glycine
N-Formimino-glutamate
Glutamate-formimino-transferase
Tetrahydrofolate
Glutamate
N5-N10-MethenylTHF reductase
NADP
NADPH
(CH2=O)
HN
N
N
HN
NR
H2N
O HC
N5,N10-MethenylTetrahydrofolate
(HCOOH)
HN
N
N
HN
HNR
H2N
O
N5-FormiminoTetrahydrofolate (HCOOH)
HCNH
Histidine
N5-FormiminoTHF cyclodeaminase
NH4
ATP
ADP+ Pi
HN
N
N
HN
HNR
H2N
O
N5-FormylTetrahydrofolate (HCOOH)
HCO
HN
N
NH
HN
NR
H2N
O
N10-FormylTetrahydrofolate (HCOOH)
ATP
ADP+ Pi
N10-FormylTHF
isomerase
HC
O
Tetrahydrofolate
HC
O
OFormate
+ ATP
ADP+ Pi
N10-FormylTHF
synthetase
N5,N10-MethyleneTHF
reductase
NADHNAD
HN
N
N
HN
HNR
H2N
O
N5-MethylTetrahydrofolate
(CH3OH)
CH3
Methyl-cobalamin
Cobalamin
Methioninesynthase
Tetrahydrofolate
HN
N
N
N
HNR
H2N
O
HN
N
N
N
HN
H2N
OR
H
HHNADPNADPH
Folic Acid Dihydrofolate
Dihydrofolatereductase
NADP
NADPHDihydrofolate
reductase
Glucose
3-phosphoglycerate
3-phospho-hydroxypyruvate3-phosphoserine
Purine Synthesis
HN
HCN
C
CC
N
CH
N
O
H
N10-formylTHFN10-formyl
THF
Aspartateamino group
Glutamineamide nitrogen
GlycineCO2
Hypoxanthine
O
OHOH
CH2OP
O
O
O H
α-D-Ribose-5-phosphate
ATP AMP
Ribose phosphatepyrophosphokinase
O
OHOH
CH2OP
O
O
O H
OOH P
O
O
O P
O
O
O
5-Phosphoribosyl-α-1-pyrophosphate
(PRPP)Glutamine
+ H2OGlutamate
+ PPi
PRPP Glutamylamidotransferase
O
OHOH
CH2OP
O
O
O NH3
H
β-5-Phosphoribosylamine
ATP+ Glycine
ADP+ Pi
GAR synthetase
O
OHOH
CH2OP
O
O
O NH
H
Glycinamideribonucleotide (GAR)
ONH3
N10-formylTHFTHF
GARtransformylase
O
OHOH
CH2OP
O
O
O NH
H
Formylglycinamideribonucleotide (FGAR)
ONHGlutamine
+ ATPGlutamate+ ADP + Pi
FGAM synthetase
O
OHOH
CH2OP
O
O
O NH
H
Formylglycinamidineribonucleotide (FGAM)
HNNH
ATP
ADP+ Pi
AIR synthetase
O
OHOH
CH2OP
O
O
O
H
5-Aminoimidazoleribonucleotide (AIR)
N
N
H2N
O HO H
CO2+ ATP ADP + Pi
AIR carboxylase
O
OHOH
CH2OP
O
O
O
H
5-Carboxyaminoimidazoleribonucleotide (CAIR)
N
N
H2N
Aspartate+ ATP ADP + Pi
SAICAR synthetase
O
O
O
OHOH
CH2OP
O
O
O
H
N-succinyl-5-aminoimidazole4-carboxamide ribonucleotide(SAICAR)
N
N
H2N
NH
OO
O
O
O
Fumarate
Adenylosuccinatelyase
O
OHOH
CH2OP
O
O
O
H
5-Aminoimidazole4-carboxamide ribonucleotide(AICAR)
N
N
H2N
H2N
O
N10-formylTHFTHF
AICARtransformylase
O
OHOH
CH2OP
O
O
O
H
N
N
NH
H2N
O
H
O
5-Formaminoimidazole4-carboxamide ribonucleotide(FAICAR)
H2O
IMPcyclohydrolase
O
OHOH
CH2OP
O
O
O
H
N
NHN
N
O
Inosinemonophosphate
(IMP)
Purine Synthesis (continued)
O
O
OHOH
CH2O
HN
N N
N
O
P
O
O
InosineMonophosphate
(IMP)
Adenylosuccinatemonophosphate
Fumarate
Adenylo
succ
inat
e
synth
etase
NH3
O
O
OO
Aspartate
GTP
GDP+ Pi
O
O
OHOH
CH2O
N
N N
N
P
O
O
HN
O
O
OO
Adenylosuccinatelyase
O
O
O
O
O
O
OHOH
CH2O
N
N N
N
NH2
P
O
O
AdenosineMonophosphate
(AMP)
Inosine monophosphate
dehydrogenase
NAD+ H2O
NADH
O
O
OHOH
CH2O
HN
NH
N
N
O
P
O
O
O
Xanthosinemonophosphate(XMP)
Glutamine+ ATP
Glutamate+ AMP + PPi
XMP-glutamineamidotransferase
(GMPsynthetase)
O
O
OHOH
CH2O
HN
N N
N
O
P
O
O
H2N
GuanosineMonophosphate
(GMP)
O
OH
CH3
O
CH3
CH3
O
HOO
Mycophenolic acid (MPA)
O
O
OHOH
CH2O
NH
N N
N
O
P
O
O
IMP dehydrogenaseintermediate
SCH2
Enzyme
Nucleotide Conversion Processes
AMPdeaminase
O
O
OHOH
CH2O
N
N N
N
NH2
P
O
O
AdenosineMonophosphate
(AMP)
O
O
OHOH
CH2O
HN
N N
N
O
P
O
O
InosineMonophosphate
(IMP)
H2O NH4
Adenylosuccinatesynthetase
NH3
O
O
OO Aspartate
GTP
GDP+ Pi
Adenylosuccinatemonophosphate
O
O
OHOH
CH2O
N
N N
N
P
O
O
HN
O
O
OO
Fumarate O
O
O
O
Adenylosuccinatelyase
O
O
OHOH
CH2O
N
N N
N
NH2
P
O
O
AdenosineMonophosphate
(AMP)
AMP
ADPATP
ADPAdenylatekinase
GMP
ADPATP
GDPGuanylatekinase
GDP
ADPATP
GTPNucleosidediphosphatekinase
O
O
OHOH
CH2O
N
N N
N
NH2
P
O
O
AdenosineMonophosphate
(AMP)
O
OHOH
CH2HO
N
N N
N
NH2
Adenosine
ADPATP
Adenosinekinase
Pyrimidine Synthesis
N
HN
O
O
O
O
HOC
O
O Carbamoylphosphatesynthetase II
Glutamine+ 2 ATP
Glutamate+ 2 ADP + Pi
NH2
COO
P OO
OBicarbonateAspartate
transcarbamoylasePi
AspartateNH2
CON
H
O
O
O
O
Carbamoylaspartate
NH
NH
O
O
O
ODihydroorotase
Dihydroorotate
H2O
CoQ
CoQH2
Dihydroorotatedehydrogenase
NH
NH
O
O
O
O
O
OHOH
CH2OP
O
O
O H
O P
O
O
O P
O
O
O
PRPPPPi
O
O
OHOH
CH2OP
O
O
OrotidineMonophosphate
Orotatephosphoribosyl
transferase
CO2
N
HN
O
OO
O
OHOH
CH2OP
O
O
UridineMonophosphate
(UMP)
OMPdecarboxylase
Orotate
N
O
HN
O
CF3 HN
O
CF3CN
CH3
HO A77 1726Leflunomide
ADPATP
Nucleosidediphosphate
kinase
ADPATP
Uridinylatekinase
N
HN
O
OO
O
OHOH
CH2OP
O
O
UridineMonophosphate
(UMP)
N
HN
O
OO
O
OHOH
CH2OP
O
O
UridineDiphosphate
(UDP)
P
O
O
ON
HN
O
OO
O
OHOH
CH2OP
O
O
UridineTriphosphate
(UTP)
P
O
O
OP
O
O
O
Glutamine+ ATP
Glutamate+ ADP + Pi
CTP synthetase
N
N
OO
O
OHOH
CH2OP
O
O
CytidineTriphosphate
(CTP)
P
O
O
OP
O
O
O
NH2
Thymidine Synthesis
NADPH NADPN
HN
O
OO
O
OHOH
CH2OP
O
O
UridineTriphosphate
(UTP)
P
O
O
OP
O
O
OPPi
dUTPPyrophosphatase
Ribonucleotidereductase
N
HN
O
OO
O
OH
CH2OP
O
O
DeoxyUridineTriphosphate(dUTP)
P
O
O
OP
O
O
ON
HN
O
OO
O
OH
CH2OP
O
O
DeoxyUridinemonophosphate
(dUMP)
N5,N10-MethyleneTetrahydrofolate
Dihydrofolate
N
HN
O
OO
O
OH
CH2OP
O
O
Thymidinemonophosphate
(dTMP)
CH3
Thymidylatesynthase
N
HN
O
OO
O
OH
CH2OP
O
O
5-Fluoro-deoxyuridylatemonophosphate(FdUMP)
F
NH
HN
O
O
F
5-Fluorouracil
Regulation of Nucleotide Synthesis
O
OHOH
CH2OP
O
O
O H
α-D-Ribose-5-phosphate
Rib
ose-
5-ph
osph
ate
pyro
phos
phok
inas
e
O
OHOH
CH2OP
O
O
O
O
OH
P
O
O
O P
O
O
O5-Phosphoribosyl-α-1-pyrophosphate
(PRPP)
O
OHOH
CH2OP
O
O
O
H
N
N
Inosinemonophosphate
(IMP) HN
N
O
PR
PP
Glu
tam
ylam
idot
ran
sfer
ase
5-Phospho-ribosylamine
Inosine monophosphate
dehydrogenaseAdenylo
succ
inat
e
synth
etase
AMP GMP
ADP GDP
ATP GTP
Car
bam
oyl
phos
phat
esy
nth
etas
e II
Asp
arta
tetr
ansc
arba
moy
lase
Carbamoylphosphate
Carbamoylaspartate
CO2 + Glutamine + 2 ATP
Aspartate
PRPP
UTP
CTP
TDP
Pyrimidinesynthesis
Purinesynthesis
Purine Salvage
O
OHOH
CH2OP
O
O
O H
O P
O
O
O P
O
O
O
5-Phosphoribosyl-α-1-pyrophosphate
(PRPP)
O
O
OHOH
CH2O
N
N N
N
NH2
P
O
O
AdenosineMonophosphate
(AMP)
PPi
Adenine phosphoribosyltransferase
Hypoxanthine-guaninephosphoribosyl
transferase (HGPRT)
N
N NH
N
NH2
Adenine
O
O
OHOH
CH2O
HN
N N
N
O
P
O
O
H2N
GuanosineMonophosphate
(GMP)
O
O
OHOH
CH2O
HN
N N
N
O
P
O
O
InosineMonophosphate
(IMP)
O
OHOH
CH2OP
O
O
O H
O P
O
O
O P
O
O
O
5-Phosphoribosyl-α-1-pyrophosphate
(PRPP) PPi
O
OHOH
CH2OP
O
O
O H
O P
O
O
O P
O
O
O
5-Phosphoribosyl-α-1-pyrophosphate
(PRPP) PPi
HN
N NH
N
O
H2N
HN
N NH
N
O
Hypoxanthine-guaninephosphoribosyl
transferase (HGPRT)Guanine Hypoxanthine
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Purine Breakdown
AMPdeaminase
O
O
OHOH
CH2O
HN
N N
N
O
P
O
O
H2N
GuanosineMonophosphate
(GMP)
O
O
OHOH
CH2O
N
N N
N
NH2
P
O
O
AdenosineMonophosphate
(AMP)
O
O
OHOH
CH2O
HN
N N
N
O
P
O
OInosine
Monophosphate(IMP)
H2O NH4 O
O
OHOH
CH2O
HN
NH
N
N
O
P
O
O
O
Xanthosinemonophosphate(XMP)
H2O
Pi
nucleotidase
H2O
Pi
H2O
Pi
H2O
Pi
O
OHOH
CH2HO
N
N N
N
NH2
Adenosine
O
OHOH
CH2HO
HN
N N
N
O
Inosine
O
OHOH
CH2HO
HN
NH
N
N
O
O
Xanthosine
O
OHOH
CH2HO
HN
N N
N
O
H2N
GuanosineAdenosinedeaminase
H2O NH4
nucleotidase nucleotidase nucleotidase
Pi
Purine nucleosidephosphorylase
(PNP)
O
OHOH
CH2HO O
PO
O
ORibose-1-phosphate
HN
N NH
N
O Hypoxanthine
HN
NH
NH
N
O
O
HN
N NH
N
O
H2N
GuanineXanthine
Pi
Purine nucleosidephosphorylase
(PNP)
Ribose-1-phosphate
Pi
Purine nucleosidephosphorylase
(PNP)
Ribose-1-phosphate
O2+ H2O H2O2
Xanthineoxidase Guanine
deaminase
H2ONH4
O2+ H2O
H2O2
Xanthineoxidase
HN
NH
NH
HN
O
O
Uric acid
O
Purine Excretion
Depiction of gout by James Gillray (political cartoonist and gout sufferer, c1756-1815)
HN
NH
NH
HN
O
O
Uric acid (keto form)
OHN
NH
NH
N
O
O
OH
Uric acid (enol form)
pKa = 5.4
O2+ H2O H2O2
Xanthineoxidase
HN
N NH
N
O Allopurinol
HN
NH
NH
N
O Alloxanthine
O
HN
NH
NH
HN
O
O
Uric acid
O
O2+ 2 H2O H2O2
CO2+
NH2
NH
NH
HN
O
Allantoin
O
O
H2O
Uric acid oxidase Allantoinase Allantoicase Urease
NH2
NH
O
Allantoic acid
O
NH
O
NH2OH
H2O HO
O
O
H
Glyoxalate
H2N NH2
O
H2N NH2
O
+
Urea
H2O CO2
NH4 NH4+
O
O
H3C
NH
H3C O
OH3C
OH3C
OH3C
Colchicine
Thymidine Kinase
N
HN
O
OO
O
OH
CH2OP
O
O
Thymidinemonophosphate
(dTMP)
CH3
ATP ADPN
HN
O
O
O
OH
CH2HO
Thymidine
CH3
Thymidinekinase
OCH2HO
HN
N N
N
O
H2N
Acyclovir
H2O
Pi
nucleotidase
N
N
OO
O
OHOH
CH2OP
O
O
CytidineMonophosphate
(CMP)
NH2
N
HN
O
OO
O
OHOH
CH2OP
O
O
UridineMonophosphate
(UMP)
H2O
Pi
nucleotidase
N
HN
O
OO
O
OH
CH2OP
O
O
ThymidineMonophosphate
(TMP)
H2O
Pi
nucleotidase
CH3
N
N
O
O
OHOH
CH2HO
Cytidine
NH2
N
HN
O
O
O
OHOH
CH2HO
Uridine
N
HN
O
O
O
OH
CH2HO
Thymidine
CH3
H2O NH4
Cytidinedeaminase
Pi
Uridinephosphorylase
Pi
Uridinephosphorylase
O
OHOH
CH2HO O
PO
O
ORibose-1-phosphate
Ribose-1-phosphate
NH
HN
O
O NH
HN
O
O
CH3
Uracil Thymine
Dihydrouracildehydrogenase
NADPH
NADP
NADPH
NADP
Dihydrouracildehydrogenase
NH
HN
O
O NH
HN
O
O
CH3
Dihydrouracil Dihydrothymine
Hydropyrimidinehydratase
NH
NH2
O NH
NH2
O
CH3
β-Ureidopropionate β-Ureidoisobutyrate
O
O O
O
H2O
Hydropyrimidinehydratase
H2O
β-Ureidopropionase
H2O H2O
NH4CO2 + NH4CO2 +
H3N
O
O
H3N
O
O
β-Alanine β-Aminoisobutyrate
CH3
β-Ureidopropionase
Aminotransferase
α-Ketoglutarate
Glutamate
α-Ketoglutarate
Glutamate
O
O
O
O
O
O
CH3
Malonicsemialdehyde
Methylmalonicsemialdehyde
CoA-SH + NAD
NADH
CoA-SH + NAD
NADH
O
O
O
O
O
O
CH3Malonyl-CoA
Methylmalonyl-CoA
S CoA S CoA
Pyrimidine Breakdown
Ribonucleotide Reductase
Escherichia coli ribonucleotide reductase R2 (catalytic subunit) dimer (pdb ID 1RIB)
NADPH NADPO
O
OHOH
CH2OP
O
O
NucleotideTriphosphate
(NTP)
P
O
O
OP
O
O
O
Ribonucleotidereductase
O
O
OH
CH2OP
O
O
DeoxynucleotideTriphosphate(dNTP)
P
O
O
OP
O
O
OBase Base
Ribonucleotide Reductase Mechanism
Ribonucleotide Reductase Regulation
O
Tyr122
Fe3+ Fe3+
O2–
OO
Glu115
O
O
OHOH
CH2OP
O
OP
O
O
O
Ribonucleotidereductase
Base
H
(R1) Enzyme S
O
O
OHOH
CH2OP
O
OP
O
O
O Base
(R1) Enzyme SH
SH SH
O
O
OH2OH
CH2OP
O
OP
O
O
O Base
(R1) Enzyme SH
S S H
O
O
HOH
CH2OP
O
OP
O
O
O Base
(R1) Enzyme S
S S
H
O
O
HOH
CH2OP
O
OP
O
O
O Base
(R1) Enzyme S
S S
H
NH
NH2
O
HO Hydroxyurea
R1
R2
R1
R2
R1
R2
Specificity
Activity
Hexamerization
R1
R2
Specificity
Activity
Hexamerization
ATPdATPdGTPdTTP
(d)NTP
R1
R2
ATPdATP R1
R2
Specificity
Activity
Hexamerization
(d)NTP
R1
R2
(d)ATP
R1
R2
R1
R2
R1
R2
Specificity
Activity
Hexamerization
(d)NTP
R1
R2
(d)ATP
ATP R1
R2
R1
R2
R1
R2
Specificity
Activity
Hexamerization
(d)NTP
R1
R2
(d)ATP
ATP
R1
R2
R1
R2
dCTP dUTP
dCTP dTTP
Deoxycytidinedeaminase
(slow)
Active dimer Active tetramer
Inactive tetramer
Active hexamer
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